Project Summary: Breast cancer is the most common cancer in women and responsible for over 40 000 deaths in the United States each year, therefore novel and more effective therapies are urgently needed. Initial experience with immune checkpoint inhibition in breast cancer has demonstrated modest responses, although durable responses have been observed. A critical barrier in developing immunotherapies in breast cancer is the development of predictive biomarkers of response and biologically driven immunotherapy combinations. This proposal will investigate will investigate novel translational approaches to overcoming immunotherapy- resistance in breast cancer. In Specific Aim 1, I hypothesize that inhibition of cyclin dependent kinase (CDK) 4/6 will result in recruitment of tumor infiltrating lymphocytes (TILs) in estrogen receptor (ER) positive breast cancer, and will result in higher responses when a programmed cell death ligand 1 (PD-L1) inhibitor is added. This aim will focus on ER-positive breast cancer, a subtype of breast cancer that is considered ?non-inflamed? or ?immunogenetically cold?, and where responses to single agent immune checkpoint inhibition has not demonstrated significant responses. In Specific Aims 2, I hypothesize that chemotherapy with or without immune checkpoint inhibition will upregulate hypoxia inducible factor 1 (HIF1) -alpha, and downstream immune-evasion genes in patients with triple negative breast cancer (TNBC). While TNBC appears to have a more ?inflamed? immune phenotype than ER-positive breast cancer, responses are still modest, and predictive biomarkers are urgently needed as well as rational drug combinations. The data generated from this proposal will allow me to perform additional research requiring RO1 funding, including validation of biomarkers of these pathways in larger studies, novel immunotherapy-based combinations, translational discovery of cancer- immune cell interactions, and ultimately improve outcomes for patients with breast cancer. Johns Hopkins houses several laboratory and clinical researchers, and provides me with an ideal environment to conduct my research, including clinical, administrative, and research support. My background in clinical and translational breast cancer research, including experience in collaborating with laboratory scientists and biomarker development, poise me to successfully obtain my immediate goals including training in the fields of cancer immunology, immunotherapeutic drug development, and bioinformatics. To this end, under the mentorship of Dr. Elizabeth Jaffee and Vered Stearns, renowned translational investigators in cancer immunology and breast cancer, respectively, I have assembled an advisory committee including bioinformatics (Dr. Leslie Cope), and immunotherapy drug development (Dr. Nilo Azad). To supplement my curriculum I plan on completing immunology courses at Johns Hopkins, and bioinformatics workshops through Cold Spring Harbor. This career development plan will poise me to obtain the expertise necessary to eventually become a leader in the field and bring practice changing immune-based paradigms for patients with breast cancer.